Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal fibrotic lung disease for which there is no effective therapy. IPF fibrotic progression is characterized by the relentless spread of fibrosis from scarred alveoli into normal adjacent alveolar units. Our studies indicate that there is a distinct IPF fibroblast phenotype characterize by aberrant integrin signaling leading to pathological activation of proliferation signaling pathways. We have discovered that IPF lung tissue harbors pathologic mesenchymal progenitor cells (MPCs) that are a cell-of-origin for IPF fibroblasts. Despite this discovery, the detailed mechanism(s) leading to the genesis and maintenance of IPF MPCs in the IPF lung and their differentiation to IPF fibroblasts remain unclear. We have found that IPF MPCs contain high levels of the calcium-binding protein S100A4 in the nucleus where it exists in a complex with histone deacetylase 4 (HDAC4). HDAC4 epigenetically regulates gene expression and has been implicated in stem cell and fibroblast differentiation. We have found that the S100A4/HDAC4 nuclear complex promotes IPF MPC propagation while suppressing differentiation. On the basis of these findings, we hypothesize that the S100A4/HDAC4 nuclear complex functions to maintain and promote the expansion of the IPF MPC population in the IPF lung. Recent studies have defined a critical role for a stiff fibrotic matrix in programming fibroblasts to acquire fibrotic properties and highlight the importance of the pathologic matrix as a driver of the progressive fibrosis in IPF. However, the role of the fibrotic matrix in directing PF MPC differentiation has not yet been examined. We hypothesize that a stiff fibrotic matrix directs IPF MPC differentiation to disease-mediating fibroblasts. This is based on exciting preliminary studies indicating that in response to interaction with a stiff matrix, the S100A4/HDAC4 nuclear complex becomes depleted and this is associated with IPF MPC differentiation. In the case of S100A4, contact with a stiff matrix promotes S100A4 translocation to the cytoplasm, where it associates with myosin IIA. The loss of nuclear HDAC4, triggered by contact with a stiff matrix, involves a decrease in the function of the a2 integrin/PP2A phosphatase axis. Our studies support a model where the S100A4/HDAC4 nuclear complex promotes IPF MPC proliferation and maintenance of IPF MPCs in the IPF lung. However, as fibrosis progresses IPF MPCs contact matrices of increasing degrees of stiffness. This triggers loss of the S100A4/HDAC4 nuclear complex and IPF MPC differentiation. We suggest that expansion of the IPF MPC population and subsequent differentiation fuels IPF fibrotic progression. To test our hypotheses we will: Aim 1: Determine the role of the S100A4/HDAC4 nuclear complex in regulating IPF MPC proliferation and suppression of differentiation. Aim 2: Analyze the role of matrix stiffness in regulating IPF MPC differentiation. Aim 3. Analyze the role of S100A4/HDAC4 in the ability of IPF MPCs to drive fibrotic progression in vivo employing the adoptive transfer model using immune-deficient mice.